According to the site of principal lesions, nephritis is classified into glomerulonephritis, interstitial nephritis and pyelonephritis, for instance. The most representative of all is glomerulonephritis in which the glomerular tuft is the affected site. Today, nephritis is synonymous with glomerulonephritis (Medical Dictionary, 1st ed., 570, 1987).
Histopathological findings which are most frequently obtained in human glomerulonephritis and considered to be of prognostic importance are mesangial cell proliferation and hyperplasia of the matrix produced by mesangial cells (hereinafter referred to as mesangial matrix). These findings are noted in nearly all types of proliferative glomerulonephritis, inclusive of IgA nephropathy, membranous proliferative glomerulonephritis, and lupus nephritis, in common (Iida: Kindney and Dialysis, 35, 505-509, 1993). And as the mesangial cell proliferation and associated production of mesangial matrix progress, the glomeruli fall into a terminal stage, so call glomerulosclerosis. Therefore, any compound that inhibits mesangial cell proliferation and production of mesangial matrix is of great value as a therapeutic agent for glomerulonephritis.
Two processes are known for mesangial cell proliferation in glomerulonephritis. In the first process, the complement, platelets, and infiltrating cells are involved. Thus, deposition of the immune complexes produced by immunological mechanisms on the glomeruli takes place in situ and activation of the complement and platelets and infiltration of macrophages and neutrophils then occur. These cells release a variety of growth factors and cytokines to activate the mesangial cells and stimulate their proliferation. The second process is a process wish which mesangial cells themselves are associated. Thus, it is a process in which activated mesangial cells themselves release a variety of growth factors and cytokines and the cells releasing them and the adjacent mesangial cells become activated or proliferate. Thus, mesangial cells are activated and proliferate through a complex system consisting of a plurality of processes.
Therefore, when the treatment of glomerulonephritis is considered, it is inconceivable that the mesangial cell proliferation can be sufficiently inhibited even if a given stage in first process mentioned above, for example the stage mediated by the complement and platelets, is inhibited. In fact, it is reported that administration of an antiplatelet drug alone is therapeutically little effective for human nephritis in active stage (Dohi et al., Clinics All-round, 38, 865-870, 1989).
It is known that, among natural substances of the plant origin, there exist compounds having antinephritic activity. For example, the usefulness of pentacyclic triterpene derivatives in the treatment of nephritis and other diseases is indicated in Japanese Laid-Open S61-37749 (an oleanene derivative), Japanese Laid-Open S61-85344 (an oleanene derivative), Japanese Laid-Open H2-73012 (a bryonolic acid derivative), Japanese Laid-Open H4-290846 (a bryonolic acid derivative), and Japanese Laid-Open S61-43141 (a lupane derivative). However, there is no disclosure of an experimental example demonstrating the utility of such compounds in the treatment of nephritis, nor is there a suggestion that they ever have mesangial cell proliferation inhibitory activity.
Hederagenin (3.beta.,23-dihydroxyolean-12-en-28-oic acid) according to the present invention is a pentacyclic triterpene derivative available from natural sources such as Sapindus mukorossi, Hedera rhombea, Hedera helix, Fatsia japonica, etc. Hederagenin is known to have hypotensive, antispasmodic (Ann. Pharm. Fr., 30, 555, 1972), hair growth-promoting, dermal aging inhibitory (FR 2669225), antimycotic (Ann. Pharm. Fr., 38, 545, 1980), antiinflammatory (Chem. Pharm. Bull., 28, 1183, 1980), antitrematoid (Rastit. Resur., 28, 103, 1992), antiulcer, antiallergic (Proc. Asian. Symp. Med. Plants Spices, 4th, Meeting Date 1980, Volume 1, 59), anti-suntan (Japanese Laid-Open H1-42411), deodorant, and hyperhidrosis inhibitory (FR 2541895), and other activities but it is not known that the compound is useful for the treatment of nephritis.
As hederagenin derivatives, the following compounds (1)-(15) are already known but it is not known whether they are of use as medicines for the treatment of nephritis or other diseases.
(1) 3.beta.-Hydroxy-23(4.alpha.)-acetoxyolean-12-en-28-oic acid (Chem. Pharm. Bull., (1976), 24(6), 1314). PA0 (2) 3.beta.-Hydroxy-23(4.alpha.)-methoxyolean-12-en-28-oic acid (Chem. Pharm. Bull., (1976), 24(5), 1021). PA0 (3) 3.beta.,23(4.alpha.)-diacetoxyolean-12-en-28-oic acid (J. Chem. Soc., Chem. Commun., (1983), (17), 939). PA0 (4) 3.beta.,23(4.alpha.)-dibenzoyloxyolean-12-en-28-oic acid (Bull. Soc. Roy. Sci. Liege, (1973), 42(5-6), 245). PA0 (5) 3.beta.,23(4.alpha.)-diformyloxyolean-12-en-28-oic acid (CAS, Registry No.=6055-17-0). PA0 (6) Methyl 3.beta.,23(4.alpha.)-dihydroxyolean-12-en-28-oate (J. Chem. Soc., Chem. Commun., (1981), (21), 1136). PA0 (7) Methyl 3.beta.-hydroxy-23(4.alpha.)-acetoxyolean-12-en-28-oate (Phytochemistry, (1984), 23(3), 615). PA0 (8) Methyl 3.beta.-hydroxy-23(4.alpha.)-methoxyolean-12-en-28-oate (Chem. Pharm. Bull., (1979), 27(10), 2388). PA0 (9) Methyl 3.beta.-acetoxy-23(4.alpha.)-hydroxyolean-12-en-28-oate (Tetrahedron, (1993), 49(33), 7193). PA0 (10) Methyl 3.beta.-benzoyloxy-23(4.alpha.)-hydroxyolean-12-en-28-oate (Tetrahedron, (1993), 49(33), 7193). PA0 (11) Methyl 3.beta.-methoxy-23(4.alpha.)-hydroxyolean-12-en-28-oate (Chem. Pharm. Bull., (1982), 30(9), 3340). PA0 (12) Methyl 3.beta.,23(4.alpha.)-diacetoxyolean-12-en-28-oate (Chem. Pharm. Bull., (1982), 30(9), 3340). PA0 (13) Methyl 3.beta.-acetoxy-23(4.alpha.)-methoxyolean-12-en-28-oate (Chem. Pharm. Bull., (1972), 20(9), 1935). PA0 (14) Methyl 3.beta.,23(4.alpha.)-dibenzoyloxyolean-12-en-28-oate (Bull. Soc. Roy. Sci. Liege, (1973), 42(5-6), 245). PA0 (15) Methyl 3.beta.,23(4.alpha.)-dimethoxyolean-12-en-28-oate (Indian J. Chem., Sect. B. (1990), 29B(5), 425). PA0 (1) R.sup.1 is hydroxy or methoxy, R.sup.2 is hydrogen, and R.sup.3 is hydrogen, acetyl, or methyl. PA0 (2) R.sup.1 is hydroxy and each of R.sup.2 and R.sup.3 is formyl, acetyl, or benzoyl. PA0 (3) R.sup.1 is methoxy, R.sup.2 is acetyl, and R.sup.3 is hydrogen, acetyl, or methyl. PA0 (4) R.sup.1 is methoxy, R.sup.2 is benzoyl, and R.sup.3 is hydrogen or benzoyl. PA0 (5) R.sup.1 is methoxy, R.sup.2 is methyl, and R.sup.3 is hydrogen or methyl. PA0 (1) Compounds in which R.sup.1 is hydroxy, acyloxyalkoxy, phenylalkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, di(hydroxyalkyl)aminoalkoxy, (alkoxyalkyl)amino, halogen-substituted phenylamino, (dialkylaminoalkyl)amino, di(hydroxyalkyl)aminoalkyl!amino, (carboxyalkyl)amino, (alkoxycarbonylalkyl) amino, (cyanoalkyl) amino, or di-amino-substituted triazinylalkylamino, R.sup.2 is hydrogen, and R.sup.3 is hydrogen. PA0 (2) Compounds in which R.sup.1 is hydroxy, (alkoxyalkyl)amino, halogen-substituted phenylamino, (dialkylaminoalkyl)amino, di(hydroxyalkyl)aminoalkyl!amino, (alkoxycarbonylalkyl)amino, or (cyanoalkyl)amino, R.sup.2 is acetoxy, and R.sup.3 is acetoxy. PA0 (3) Compounds in which R.sup.1 is phenylalkoxy, R.sup.2 is hydroxy, (alkoxycarbonylalkyl)carbamoyl, or (alkoxyalkyl)carbamoyl, and R.sup.3 is phenylalkyl. PA0 (4) Compounds in which R.sup.1 is hydroxy, R.sup.2 is (alkoxycarbonylalkyl)carbamoyl or (alkoxyalkyl)carbamoyl, and R.sup.3 is hydrogen. PA0 (5) Compounds in which R.sup.1 is hydroxy or acyloxyalkoxy and R.sup.2 and R.sup.3 taken together represents carbonyl.